Mechanistic understanding of the lifecycle of a circulating hybrid cell

对循环混合细胞生命周期的机制理解

• 批准号: 10316094
• 负责人: Summer Lynne Gibbs
• 金额: $ 63.27万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10316094
• 关键词: Address; Aging; Architecture; Area; Behavioral; Binding Sites; Biological; Biological Assay; Biology; Blood Circulation; Blood specimen; Cancer Etiology; Cells; Cellular biology; Cessation of life; Clinical; Colorectal Cancer; Computer Analysis; Copy Number Polymorphism; DNA Sequence Alteration; Development; Diagnosis; Disease; Disseminated Malignant Neoplasm; Distant; Effector Cell; Elements; Evaluation; Evolution; Fluorescence; Foundations; Gene Expression; Human; Hybrid Cells; Hybrids; Immunofluorescence Immunologic; Incidence; Investigation; Knowledge; Link; Location; Malignant Neoplasms; Mediating; Melissa; Micrometastasis; Molecular; Nature; Neoplasm Circulating Cells; Neoplasm Metastasis; Outcome; Patient Care; Patients; Periodicity; Phase; Phenotype; Population; Primary Neoplasm; Property; Prospective Studies; Proteins; Publishing; Recurrence; Reporting; Risk; Role; Sampling; Seeds; Site; Spatial Distribution; Technology; Testing; Therapeutic; Time; Tumor Biology; Tumor stage; Work; Zebrafish; cancer care; cohort; colon cancer patients; falls; in vivo; innovation; insight; longitudinal analysis; metastatic process; migration; multidisciplinary; multiple omics; neoplastic; neoplastic cell; novel; novel strategies; peripheral blood; stem cells; stem-like cell; technology development; treatment response; treatment stratification; tumor; tumor growth; tumor progression

Metastatic disease accounts for >90% of cancer-related deaths worldwide, yet this phase of tumor progression is the least biologically understood. The consequence of this lack of knowledge is that we do not have the appropriate therapeutic arsenal to defeat metastatic cancer. New revelations for colorectal cancer point to shed neoplastic cells into peripheral blood even from early stage tumors, suggesting this is why some early stage tumors recur despite seemingly successful treatment. However, whether all early stage primary tumors shed neoplastic cells, or if only subsets of more aggressive neoplastic cells garner ability to disseminate is not known. This highlights the critical gap in knowledge of the mechanisms underlying neoplastic cell dissemination leading to distant disease. Identifying the key features within the lifecycle of a disseminated tumor cell will unravel this important step in tumor progression with potential to influence management of cancer care. Our study leverages newly developed state-of-the-art phenotypic analyses of key attributes of a recently discovered neoplastic hybrid cell in primary tumors and in peripheral blood, termed circulating hybrid cells (CHCs), supported by cutting-edge computational analyses. Interestingly, CHCs harbor tumor-initiating properties implying that they have high potential as effectors of metastatic tumor seeding. We will detail cells poised to disseminate from the primary tumor into circulation and seed metastatic sites combining protein, multi-omic analyses and functional behavioral analyses. A focus on a stage II and late stage colorectal cancer cohorts support analyses across the disease axis, with an emphasis on stage II CRC patients with undetected micrometastases at the time of diagnoses. Evaluation of the lifecycle of the hybrid cell from primary tumor to dissemination will provide biologic insight into the metastatic process with great potential to impact the management and care of patients with cancer.

转移性疾病占全球癌症相关死亡的90%，但肿瘤进展的这一阶段 是生物学上所知最少的。这种缺乏知识的后果是，我们没有 战胜转移性癌症的适当治疗手段。结直肠癌的新启示指向摆脱 肿瘤细胞甚至从早期肿瘤进入外周血，这表明这就是为什么一些早期肿瘤 尽管治疗看似成功，肿瘤还是会复发。然而，是否所有早期原发肿瘤都会脱落 肿瘤细胞，或者是否只有更具侵袭性的肿瘤细胞亚群获得传播能力尚不清楚。 这凸显了人们对肿瘤细胞扩散机制的认识上的严重差距。 远方的疾病。识别播散性肿瘤细胞生命周期中的关键特征将揭开这一点 在肿瘤进展中的重要一步，有可能影响癌症护理的管理。我们的研究利用 一种新发现的肿瘤杂交瘤关键属性的最新表型分析 原发肿瘤和外周血中的细胞，称为循环杂交细胞(CHC)，由尖端技术支持 计算分析。有趣的是，CHC具有引发肿瘤的特性，这意味着它们有很高的 有可能作为转移性肿瘤种植的效应者。我们将详细介绍准备从初级 结合蛋白质、多组学分析和功能行为学的肿瘤进入循环和种子转移部位 分析。对II期和晚期结直肠癌队列的关注支持对疾病的分析 Axis，重点是在诊断时有未发现微转移的II期CRC患者。 对杂交细胞从原发肿瘤到扩散的生命周期的评估将为我们提供对 转移过程具有极大的潜在影响癌症患者的管理和护理。